Various therapeutic delivery devices and systems which reportedly provide some or all of the above-mentioned advantageous features are known in the art. Such delivery devices and systems may be classified according to their delivery means, such as, e.g., diffusional, osmotic, elastomeric, or mechanically facilitated devices, and erodible or nonerodible systems. The novel devices of the present invention are nonerodible diffusion systems which take advantage of Bernoulli effects to perform their function.
A major benefit of the transdermal systems such as those within the scope of the present invention is the elimination of the characteristic swings in medicament concentration within the body of the patient that are common when parenteral administration of medicaments is employed. It is common to overmedicate so that the body will receive enough medication to allow long term effectiveness. Unfortunately, high initial doses or widely fluctuating dose levels, may cause adverse side effects within the body of the patient. Transdermal methods of applying medicament provide a relatively long term and continuous supply of the medicament and thus eliminate the need for the over medication peak necessary with intravenous administration. Transdermal devices such as those embodied by the present invention have the further advantage over intravenous methods in that no trauma results from use of these devices.
Problems associated with oral methods of supplying medicaments in mammalian systems are also overcome by transdermal and transmucosal devices. Lesions of the tongue, esophagus and stomach have been shown to often accompany constant use of such oral medicaments as aspirin and in some cases this use has been shown to cause in situ tumors. Transdermal devices avoid this potential problem by fixing the site of medicament transfer on the skin or a mucous membrane and by supplying the medicament in lower and constant concentrations. These devices provide the additional benefit of localized treatment, i.e., the device may be affixed directly to the afflicted region to provide specific treatment of regional disorders such as tumors.
In order to ameliorate the above mentioned problems, various under the skin implants, pumps and strips of medicated materials have been heretofore proposed. Although these devices are represented to release medicament at a constant concentration level for a predetermined period of time, they are costly, require careful monitoring by a physician and they often pose an added danger of serving as a focus for bacterial infection.
There are also other systems for transferring medicament across dermal or mucosal surfaces that are more nearly related to the present invention, because they rely on diffusion for the subcutaneous transfer of active agent to the circulating system at the interface between the applicator and the patient's skin, although each employs different driving forces to supply the chemical energy necessary for effective transdermal transfer from the Bernoulli effects on which the present invention depends. In this invention, Bernoulli effects are availed of to apply concentrated solutions of the active agent to the skin at a rate and pressure sufficient for optimal absorption. No previously disclosed transdermal delivery device operates in this manner.
Many patented devices rely exclusively on diffusion for transporting active agents. Such devices do not provide the efficient directed flow of the agent against the skin that can be provided by the present use of the Bernoulli effect. Often such devices are designed to release agents into a liquid containing environment within the body, such as the gastrointestinal tract, or if used for transdermal applications, these devices must include some type of cover to prevent the agent from being released to the surrounding environment, whether by evaporation or other means. The present invention is instead designed for unidirection transfer of medicament against the skin or mucous membrane to which it is attached. Typical diffusion-type devices are described in the following paragraphs.
U.S. Pat. No. 4,291,015 describes a polymeric diffusion matrix containing a vasodilator comprising a polar plasticizer, such as glycerol, a polymeric matrix, and a water soluble polymer along with the vasodilator. The transdermal transfer of the active ingredient is effected by use of a diffusion concentration gradient normal to the surface of the patient's skin and the diffusion matrix. An inert backing material is affixed to the side of the device not in contact with the patient's skin.
U.S. Pat. No. 4,220,153 discloses a delivery device comprising a porous fabric impregnated with a hydrogel surrounding a chemical containing reservoir, which may include a drug and a water soluble liquid incipient. This device is designed to be used primarily in an aqueous liquid containing environment within the body since the diffusional mechanism requires bidirectional mass transfer.
U.S. Pat. No. 4,308,867 describes a diffusion device which is comprised of an inner support, a polymeric layer containing an active agent, and an outer polymeric membrane. The two polymeric layers are chosen based on their relative diffusion coefficients and solubilities so that the rate of release of the active agent into the external environment can be controlled. Here again the mechanism of release is only diffusion.
Many patented devices rely on osmotic pumping to supply the pressure necessary for the system to operate. For example, U.S. Pat. No. 4,008,719 discloses such a device wherein the active agent is contained in an internal compartment which is surrounded by plural semipermeable laminae. The laminae allow unhindered passage of the driving fluid but prevent passage of the active agent, thus setting up a net transfer of material into the inner compartment and supplying osmotic pressure. Such devices suffer from the disadvantage of relative structural complexity and are expensive to make because they require sophisticated manufacturing techniques; this in turn makes them expensive to use.
Another means for supplying the force necessary to cause the active agent to be released from transdermal applicators is through mechanical pressure. Several patented devices rely upon swellable polymers which when contacted with fluid expand causing a decrease in the volume available for the active agent. The resulting pressure increase drives the agent from the system into the desired environment. Examples of such devices are disclosed in U.S. Pat. No. 4,320,759, U.S. Pat. No. 4,350,271 and U.S. Pat. No. 4,223,061.